A number of different base materials have been described for the manufacture of compositions intended to achieve hemostasis on bleeding tissue. Many of these are suitable for soft tissues. For example, U.S. Pat. No. 6,060,461 describes porous particles of a polysaccharide, preferably cross-linked dextran, to promote blood clotting on soft tissue. The particles, as described, are “designed to act as a sieve to dehydrate the blood and accelerate the natural blood clotting process.” US 2009/0062233 describes a hemostat in powder form based on modified starch. U.S. Pat. No. 6,056,970 describes a polysaccharide-based matrix combined with a fibrin glue or a collagen patch containing, e.g., aprotinin, fibrinogen, and/or thrombin. U.S. Pat. No. 6,923,961 describes hemostatic compositions of derivatized CMC/polyethylene oxide (PEO) composites containing chemical hemostatic agents such as thrombin.
For use in bone, a hemostatic tamponade must adhere to the hard, moist surface of bleeding bone or cartilage while not adhering appreciably to surgical gloves and instruments. The composition must also be sufficiently moldable for easy application to the site. Optimal formulations are able to withstand the force of saline irrigation that accompanies typical surgical procedures. The durability of the composition in the in vivo environment should be sufficient for the composition to serve as an effective hemostatic tamponade at the wound site throughout the entire intraoperative period and for a sufficient time after surgery to ensure bleeding has stopped. The term “tamponade” refers to the mechanical hemostasis occurring when a material is applied to a bleeding surface to occlude the vessels or pores through which blood flows, creating a static interface between the material and the dammed blood flow. Normal clotting can then occur within this static interface. Compositions unsuitable for use as a tamponade do not adhere directly to the bleeding surface, are easily dislodged by the force of flowing blood or surgical irrigation, or are too water-soluble.
The traditional and still widely used composition for tampanade hemostasis of bone or cartilage is bone wax. Bone wax is generally made from beeswax and a softening agent such as isopropyl palmitate. Its main disadvantage is that it is nondegradable and nonabsorbable under physiological conditions. This results in undesirable effects such as inhibition of bone healing and osteogenesis and, as with any nonabsorbable foreign body implant, promoting infection, inflammation, and pain.
Several absorbable or partially absorbable alternatives to traditional bone waxes have been described. For example, U.S. Pat. No. 4,568,536, by Kronenthal, et al., and U.S. Pat. No. 4,439,420 by Mattei, et al., describe compositions featuring particulate solid materials suspended in oils and highly water soluble solid poloxamers (ie Pluronics). U.S. Pat. No. 7,989,000 by Kronenthal describes compositions containing a solid particulate fatty acid salt suspended in a liquid poloxamer along with certain other excipients. U.S. Pat. No. 5,356,629 by Sander, et al., describes a composition containing coated particles of polymethylmethacrylate in a matrix of cellulose ether, collagen, or hyaluronic acid. U.S. Pat. Nos. 7,553,913 and 7,829,616 by Wellisz, et al., describe hydrophilic water soluble waxy compositions comprising a base of a random copolymer comprising ethylene oxide and one or more other alkylene oxide(s) which may be mixed with solid particles. U.S. Pat. No. 7,914,819 by Wen, et al., describes a polymeric matrix having a polysaccharide backbone. U.S. Pat. No. 7,074,425 by Constantine, et al., describes hydrophilic polyethylene glycol based compositions consisting of a mixture of a high and a low molecular weight polyethylene glycol of HLB (hydrophilic lipophilic balance) greater than 20.
Despite the progress that has been made in this field, there remains a need for an alternative to “bone wax” that is as effective in achieving tamponade hemostasis for a suitable time while also being completely biodegradable or absorbable. Water-soluble wax-like compositions described by e.g., Wellisz (including the commercially available OSTENE) suffer from the disadvantage of not being durable under surgical conditions to maintain adequate hemostasis for a sufficient period of time. See, e.g., Holman, 2007. With the exception of traditional bone wax, water-insoluble waxes have not generally been utilized in the preparation of hemostatic tamponades because of their insolubility in the aqueous in vivo environment and their inability to be phagocytized.
The present invention overcomes these disadvantages by providing compositions based upon water-soluble wax-like substances that are formulated to maximize their durability under surgical conditions while maintaining optimal absorbability and/or degradability under physiological conditions.